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Essentials in Ophthalmology Series Editor: Arun D. Singh
Mary Qiu Editor
Neovascular Glaucoma
Current Concepts in Diagnosis and Treatment
Essentials in Ophthalmology Series Editor Arun D. Singh, Cleveland Clinic Foundation Cole Eye Institute Cleveland, OH, USA
Essentials in Ophthalmology aims to promote the rapid and efficient transfer of medical research into clinical practice. It is published in four volumes per year. Covering new developments and innovations in all fields of clinical ophthalmology, it provides the clinician with a review and summary of recent research and its implications for clinical practice. Each volume is focused on a clinically relevant topic and explains how research results impact diagnostics, treatment options and procedures as well as patient management. The reader-friendly volumes are highly structured with core messages, summaries, tables, diagrams and illustrations and are written by internationally well-known experts in the field. A volume editor supervises the authors in his/her field of expertise in order to ensure that each volume provides cutting- edge information most relevant and useful for clinical ophthalmologists. Contributions to the series are peer reviewed by an editorial board. More information about this series at https://link.springer.com/bookseries/5332
Mary Qiu Editor
Neovascular Glaucoma Current Concepts in Diagnosis and Treatment
Editor Mary Qiu Ophthalmology and Visual Science University of Chicago Chicago, IL, USA
ISSN 1612-3212 ISSN 2196-890X (electronic) Essentials in Ophthalmology ISBN 978-3-031-11719-0 ISBN 978-3-031-11720-6 (eBook) https://doi.org/10.1007/978-3-031-11720-6 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022, corrected publication 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
Contents
Neovascular Glaucoma: An Overview �������������������������������������������������� 1 Pujan Dave and Pradeep Y. Ramulu Epidemiology of Neovascular Glaucoma ���������������������������������������������� 5 Saira Khanna and Dolly S. Chang Pathophysiology of Neovascular Glaucoma������������������������������������������ 11 Qing Wang and Thomas V. Johnson Clinical Diagnosis of Neovascular Glaucoma in the Ophthalmology Office ���������������������������������������������������������������������� 23 Inas F. Aboobakar and Michael M. Lin Clinical Diagnosis of Neovascular Glaucoma in the Emergency Room������������������������������������������������������������������������������ 31 Christos N. Theophanous and Katy C. Liu Neovascular Glaucoma in Proliferative Diabetic Retinopathy������������ 37 Jing Shan, Chu Jian Ma, and Catherine Q. Sun Neovascular Glaucoma in Retinal Vein Occlusions������������������������������ 57 Nicholas A. Johnson and Atalie C. Thompson Neovascular Glaucoma in Ocular Ischemic Syndrome������������������������ 69 Zhuangjun Si and Seenu M. Hariprasad Neovascular Glaucoma in Ocular Inflammatory Disease�������������������� 75 Rachel A. Downes and Careen Y. Lowder Neovascular Glaucoma in Chronic Retinal Detachments�������������������� 79 Aaron Priluck, Loka Thangamathesvaran, and Ravi Pandit Neovascular Glaucoma in Ocular Tumors and Radiation ������������������ 87 Matthew P. Nicholas, Annapurna Singh, and Arun D. Singh Treatment Goals in Neovascular Glaucoma������������������������������������������ 97 Humberto Salazar and Swarup S. Swaminathan Panretinal Photocoagulation for Neovascular Glaucoma�������������������� 111 Anna G. Mackin, Nathalie Massamba, and Dimitra Skondra
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Anti-Vascular Endothelial Growth Factor for Neovascular Glaucoma���������������������������������������������������������������������������� 121 Narine Viruni and Cindy X. Cai Medical IOP-Lowering Therapy for Neovascular Glaucoma�������������� 131 Pathik P. Amin and Mary Qiu Trabeculectomy for Neovascular Glaucoma ���������������������������������������� 139 Kevin M. Halenda and Annapurna Singh Aqueous Shunt for Neovascular Glaucoma������������������������������������������ 151 Wesam S. Shalaby, Dilru C. Amarasekera, and Aakriti Garg Shukla Cyclophotocoagulation for Neovascular Glaucoma������������������������������ 167 Michael A. Krause and Jonathan Eisengart Micro-incisional Glaucoma Surgery for Neovascular Glaucoma�������� 177 Jacob Kanter and Mary Qiu Advancing Care in Neovascular Glaucoma������������������������������������������ 185 Mary Qiu, Aakriti G. Shukla, and Catherine Q. Sun Correction to: Aqueous Shunt for Neovascular Glaucoma. . . . . . . . C1 Index���������������������������������������������������������������������������������������������������������� 193
Contents
Neovascular Glaucoma: An Overview Pujan Dave and Pradeep Y. Ramulu
Neovascular glaucoma (NVG) is an aggressive secondary glaucoma resulting from iris and anterior chamber angle neovascularization that is most often triggered by underlying retinal ischemia. Because the etiology of angle neovascularization is often the domain of one ophthalmic subspecialty (retina), while the manifestation is the domain of another (glaucoma), the topic is both difficult to treat and to discuss academically. Also, the subject may not have been previously addressed in as much depth as done here based on historical data demonstrating poor visual outcomes in NVG eyes. The current book, which reviews the causes of NVG, while also updating us on latest methods of addressing neovascularization and safely achieving IOP-lowering, is therefore a welcome and much-needed contribution. The earliest report of what we now understand to be NVG was documented in 1871, which described an eye with elevated intraocular pressure (IOP) in the setting of intraocular hemorrhage [1]. Decades later in 1906, angiogenesis of the iris was histologically described by Coats in a patient with a central retinal vein occlusion (CRVO), and similar abnormal vessel growth was identified on the iris surface of patients with dia-
P. Dave · P. Y. Ramulu (*) Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA e-mail: [email protected]
betes in years to come [2]. A variety of names, including hemorrhagic glaucoma, rubeotic glaucoma, and congestive glaucoma, were used to describe this condition until the introduction of term “neovascular glaucoma” by Weiss in 1963 based on an improved understanding of the pathophysiology of the condition [3, 4]. In contrast to other more common glaucomas (primary open angle, pseudoexfoliation, pigment dispersion, etc.) that have similar approaches to management, NVG requires a unique treatment paradigm involving not only the control of elevated IOP, but also the control of pro-angiogenic conditions that promote neovascularization. The management of NVG has evolved significantly since its early descriptions as we have discovered new approaches to control retinal ischemia and surgically manage elevated intraocular pressure. Though NVG accounts for a minority of all glaucomas, it is aggressive and frequently refractory to medical management, requiring surgical intervention. An overlooked, but very important, aspect of NVG management is close monitoring for its development in high-risk patients [5]. While we as practitioners are often presented with the challenge of treating eyes where NVG has clearly manifested, we less often ask the question of what we might do better to avoid having patients develop NVG. It is well established that high-risk patients most commonly include those with ischemic CRVO, diabetic retinopathy, and ocular
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ischemic syndrome, but, as discussed later in this textbook, there are many other conditions in which NVG can develop. Early recognition and treatment of underlying etiologies may prevent development of NVG, or arrest and reverse the process at its earliest stages. In the past, panretinal photocoagulation (PRP) was the only option for the prevention and treatment of neovascularization, with variable success depending on the underlying condition and timing of the treatment. The advent of intravitreal antivascular endothelial growth factor (anti-VEGF) treatment, however, has drastically changed our approach and outcomes, and has become the mainstay of treatment alongside PRP for all causes of ocular neovascularization. Unfortunately, despite these interventions, many patients develop high IOP that necessitates specific IOP lowering treatment. Medical management includes topical IOP lowering agents commonly used for glaucoma management (e.g., carbonic anhydrase inhibitors, alpha-2 agonists, etc.) and oral carbonic anhydrase inhibitors when topical treatment is not sufficient. Topical corticosteroids are used in some patients to control intraocular inflammation. When medical management does not lower the IOP enough to prevent optic nerve damage, which is much more common with NVG than with other forms of glaucoma, surgery becomes necessary to control the IOP. Traditionally, surgical management of NVG includes either implantation of aqueous shunts and diode laser cyclophotocoagulation (CPC). Historically, trabeculectomy has a relatively high failure rate in NVG even with use of antimetabolites and is therefore not routinely performed [6]. Much of our knowledge about the best surgical outcomes for NVG comes from studies that were performed before the routine use of anti- VEGF medications. Moreover, the arrival and popularization of micro-incisional glaucoma surgery (MIGS) have transformed surgical glau-
P. Dave and P. Y. Ramulu
coma management, and it has not yet been extensively studied whether these novel anglebased surgeries would be effective for NVG. Given the revolutionary effect of combination anti-VEGF and PRP treatment on regression of neovascularization, some patients with NVG may obtain IOP control with MIGS alone as opposed to traditional glaucoma surgery. Certainly, aqueous shunts and diode laser CPC will remain important for particular cases, but angle-based surgeries may modify NVG management in the anti-VEGF era. This book will also review the most recent data regarding the outcomes of procedures that filter aqueous humor to the subconjunctival space (i.e., trabeculectomy)—an important question for areas of the world where the cost of certain surgical implants (i.e., aqueous shunts) may be prohibitive. Our understanding of NVG and its management have progressed tremendously since its first description in the nineteenth century. The disease remains difficult to treat in spite of these advances and ocular morbidity from NVG remains high. It is vital to rigorously evaluate both novel and conventional treatments to optimize management of this particularly challenging and refractory disease. As vascular disease becomes more prevalent, NVG, too, is likely to become more common given the associations between vascular disease and underlying ocular conditions that predispose to NVG. Retina and glaucoma specialists must work closely together to treat this condition with a combination of PRP, anti-VEGF, medical IOPlowering therapy, traditional glaucoma surgery, and possibly MIGS, catering to each patient’s individual clinical needs as our understanding of NVG becomes increasingly refined. We welcome this comprehensive discussion of a very challenging problem, with the goal that we might change our practice to prevent and/or detect NVG earlier, and to achieve better outcomes when it does present.
Neovascular Glaucoma: An Overview
References 1. Gilbert W. Beiträge zur Lehre vom Glaukom. Graefes Arch Ophthalmol. 1912;82(3):389–474. 2. Coats G. Further cases of thrombosis of the central vein. London: J. & A. Churchill; 1906. 3. Weiss DI, Shaffer RN, Nehrenberg TR. Neovascular glaucoma complicating carotid-cavernous fistula. Arch Ophthalmol. 1963;69(3):304–7.
3 4. Smith RJ. Rubeotic glaucoma. Br J Ophthalmol. 1981;65(9):606–9. 5. Hayreh SS. Neovascular glaucoma. Prog Retin Eye Res. 2007;26(5):470–85. 6. Mietz H, Raschka B, Krieglstein GK. Risk factors for failures of trabeculectomies performed without antimetabolites. Br J Ophthalmol. 1999;83(7):814–21.
Epidemiology of Neovascular Glaucoma Saira Khanna and Dolly S. Chang
1 Introduction
2 Prevalence
Neovascular glaucoma (NVG) is a form of secondary glaucoma characterized by the proliferation of fibrovascular tissue in the anterior chamber producing neovascularization of the iris (NVI) and/or neovascularization of the iridocorneal angle (NVA), which subsequently causes elevation in intraocular pressure (IOP). Retinal ischemia is the underlying etiology in more than 95% of cases and the most common causes of NVG are proliferative diabetic retinopathy (PDR), retinal vein occlusion (RVO), and ocular ischemic syndrome (OIS). NVG has a high risk of causing severe vision impairment and can result in both unilateral and bilateral blindness [1]. Because NVG occurs as the result of poorly controlled diseases, the epidemiology of NVG is closely linked to the epidemiology and treatment of its underlying diseases.
The prevalence of NVG in population-based studies has had variable reports ranging from 0.01 to 0.2% [2–6]. In West Bengal, the prevalence was 0.01% [2], 0.03% in China [6], 0.12% in the Singapore Indian Eye Study [4], and 0.2% in Nigeria [3]. Hospital-based prevalence of NVG in Nigeria was reported to be 0.3% [5]. Additionally, data from the European Union estimated that up to 300,000 people in Europe are affected by NVG, and NVG has been estimated to comprise ~3.9–5.8% of all glaucomas and 15.4% of secondary glaucomas [7, 8]. Based on a longitudinal health insurance database from Taiwan, the prevalence of NVG was shown to have increased substantially from 4.4 per 100,000 individuals in 2000 to 12.4 per 100,000 individuals in 2015 [9]. In the United States, no specific prevalence or number of individuals has been reported to have NVG in population-based studies; however, from the 2016 Intelligent Research in Sight (IRIS®) Registry, the prevalence of NVG in the dataset was 0.23 per 100 patients [10]. From hospital-based data review in Taiwan and Saudi Arabia, the overall incidence of NVG has been reported around 4.3–6.6 per 100,000 person-years [9, 11]. In Saudi Arabia, the incidence of NVG was noted to have increased from 3 per 100,000 person-year in 2002 to 12 per 100,000 person-year in 2008. With the introduc-
S. Khanna Department of Ophthalmology and Visual Science, The University of Chicago, Chicago, IL, USA D. S. Chang (*) Genentech Research and Early Clinical Development, South San Francisco, CA, USA Byers Eye Institute, Stanford University, Palo Alto, CA, USA
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 M. Qiu (ed.), Neovascular Glaucoma, Essentials in Ophthalmology, https://doi.org/10.1007/978-3-031-11720-6_2
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tion of intravitreal antivascular endothelial growth factor (anti-VEGF) therapies around 2008, the incidence of NVG in Taiwan has decreased to 1.0 per 100,000 person-year in 2012, and there has been a reduction in the number of IOP-lowering surgeries [9].
3 Risk Factors 3.1 Age NVG can affect any age group, depending on the underlying cause of the neovascularization. The most common age group affected by NVG is 60–80 years of age [12]. Based on the underlying etiology for the neovascularization, different age groups are disproportionately affected. Retinoblastoma and Coats’ disease are predominant reasons for neovascularization in the pediatric population whereas diabetes and ischemic vascular diseases predispose patients to neovascularization in older patient populations [13].
3.2 Race There does not appear to be a racial predilection for race for NVG. Any variations in prevalence or incidence in various racial groups are likely attributed to differences in the underlying etiology for the neovascularization. There is no literature investigating if race is a risk factor specifically for NVG. The underlying cause of neovascularization may differ slightly based on race [13–17]. Future investigation is warranted to determine if there is truly a difference in racial predilection in the development of NVG independent of the underlying condition.
3.3 Gender There does appear to be an overall male preponderance in both the incidence and prevalence of NVG [8, 9, 11, 18] with the occasional study showing that there is no sex predilection [5]. One study showed that the odds ratio of men
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having NVG compared to women was 2.2 [11] while others demonstrated a statistically significant difference in the prevalence between men and women (62% men compared to 37% women) [8]. Like age and race, this gender predilection may be attributed to the risk of having underlying diseases that lead to NVG in men rather than sex being an independent risk factor, since men are more likely to develop vascular diseases. It is unclear at this time whether there is a gender predisposition of developing NVG once patients have the underlying disease, however, studies examining predictors of developing NVG in PDR and CRVO, gender was not significant [19, 20].
3.4 Socioeconomic Status Lower education status has been associated with the development and severity of NVG. In a study of NVG patients conducted in Mexico, it was reported that only 20% of the patients had completed education beyond elementary school [18]. Other studies have demonstrated that there are lower odds of glaucoma (not only NVG) with increasing income level and education [9, 21]. In addition, it has been shown that poorer visual outcomes in glaucoma have been associated with lower socioeconomic status [22].
4 Prevalence Based on Etiology There are underlying etiologies for the development of NVG, and the three most common etiologies include PDR, RVO, and OIS [12, 23–27]. An extensive list of underlying etiologies that have been associated with NVG is shown in Table 1 [26].
4.1 Diabetes Mellitus Multiple studies have shown that poorly controlled diabetes mellitus is a leading cause of NVG [8, 28, 29]. The incidence of NVI has been reported to be as high as 65% in patients with PDR in a 1998
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Epidemiology of Neovascular Glaucoma Table 1 Diseases which may cause neovascularization glaucoma, adopted from Sivak-Callcott et al. [26] Retinal ischemic diseases Diabetes Central retinal vein occlusion Ocular ischemic syndrome/carotid occlusive disease Central retinal artery occlusion Retinal detachment Leber’s congenital amaurosis Coats’ disease Eales disease Sickle cell retinopathy Retinal hemangioma Persistent hyperplastic primary vitreous Norrie’s disease Wyburn Mason Carotid-cavernous fistula Dural shunt Stickler’s syndrome X-linked retinoschisis Takayasu’s aortitis Juxtafoveal telangiectasis Surgically induced Carotid endarterectomy Cataract extraction Pars plana vitrectomy/lensectomy Silicone oil Scleral buckle Neodymium: yttrium-aluminum-garnet capsulotomy Laser coreoplasty Tumors Iris: melanoma, hemangioma, metastatic lesion Ciliary body: ring melanoma Retina: retinoblastoma, large cell lymphoma Choroid: melanoma Conjunctiva: squamous cell carcinoma Radiation External beam Charged particle: proton, helium Plaques Photoradiation Inflammatory diseases Uveitis: chronic iridocyclitis, Behçet’s disease Vogt-Koyanagi-Harada syndrome Syphilitic retinitis Sympathetic ophthalmia Endophthalmitis Miscellaneous Vitreous wick syndrome Interferon alpha
study [27]. In addition, patients with a higher hemoglobin A1c are more likely to develop NVG
[30]. It has been reported that 5% of blindness in diabetics is caused by NVG [31]. It has also been reported that patients with diabetes with unilateral NVG have a 33% risk of developing NVG in the other eye [32]. In eyes with PDR after vitrectomy, up to 7.1% of males developed NVG within 1 year of vitrectomy; male sex, younger age, higher baseline IOP, and having NVG in the fellow eye were reported to be risk factors [20].
4.2 Retinal Vein Occlusions Approximately one-third of all cases of NVG can be attributed to retinal vein occlusions [33]. In addition, 20% of patients with ischemic central retinal vein occlusions (CRVO) can develop NVG with an estimated 3800 new cases per year [34]. It has been shown that retinal nonperfusion status and uncontrolled intraocular pressure predispose patients to the development of NVG [35]. In most cases, the development of NVG happens within the first 3 months from onset of disease, but may also occur later especially with the rising use of anti-VEGF injections to treat macular edema in patients with retinal vascular occlusion [36]. Risk factors for the development of NVG in RVOs include presence of RAPD, worse visual acuity on presentation, and systemic hypertension [19].
4.3 Ocular Ischemic Syndrome NVG has been reported in nearly 50% of eyes with ocular ischemic syndrome [37]. In addition, a delay from onset of symptoms to medical evaluation and severity of carotid artery stenosis has been correlated with the development of NVG [38]. These cases are typically unilateral and should always be on the differential for NVG in the elderly population.
5 Conclusion NVG is a devastating disease and may become increasingly prevalent as systemic comorbidities associated with its development such as diabetes,
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hypertension, and metabolic syndrome become more widespread. Prevention and treatment of these underlying systemic conditions as well as the ischemic retinal diseases that directly lead to NVG may help reduce both the incidence and prevalence of NVG and the associated ocular morbidity.
References 1. Rani PK, Sen P, Sahoo NK, Senthil S, Chakurkar R, Anup M, et al. Outcomes of neovascular glaucoma in eyes presenting with moderate to good visual potential. Int Ophthalmol [Internet]. 2021 Mar 21 [cited 2021 May 11]; Available from https://doi. org/10.1007/s10792-021-01789-y 2. Paul C, Sengupta S, Choudhury S, Banerjee S, Sleath B. Prevalence of glaucoma in Eastern India: the Hooghly River Glaucoma Study. Indian J Ophthalmol. 2016;64(8):578. 3. Ashaye A, Ashaolu O, Komolafe O, Ajayi BGK, Olawoye O, Olusanya B, et al. Prevalence and types of glaucoma among an indigenous African population in Southwestern Nigeria. Invest Ophthalmol Vis Sci. 2013;54(12):7410. 4. Narayanaswamy A, Baskaran M, Zheng Y, Lavanya R, Wu R, Wong W-L, et al. The prevalence and types of glaucoma in an urban Indian population: the Singapore Indian Eye Study. Invest Ophthalmol Vis Sci. 2013;54(7):4621. 5. Fiebai B, Onua AA. Prevalence, causes and management of neovascular glaucoma: a 5-year review. Open J Ophthalmol. 2018;09(01):1. 6. Baskaran M, Foo RC, Cheng C-Y, Narayanaswamy AK, Zheng Y-F, Wu R, et al. The prevalence and types of glaucoma in an urban Chinese population: the Singapore Chinese Eye Study. JAMA Ophthalmol. 2015;133(8):874–80. 7. Mocanu C, Barăscu D, Marinescu F, Lăcrăţeanu M, Iliuşi F, Simionescu C. Neovascular glaucoma—retrospective study. Oftalmologia. 2005;49(4):58–65. 8. Liao N, Li C, Jiang H, Fang A, Zhou S, Wang Q. Neovascular glaucoma: a retrospective review from a tertiary center in China. BMC Ophthalmol. 2016;16:14. 9. Lin P-A, Lee C-Y, Huang F-C, Huang J-Y, Hung J-H, Yang S-F. Trend of neovascular glaucoma in Taiwan: a 15-year nationwide population-based cohort study. Ophthalmic Epidemiol. 2020;27(5):390–8. 10. IRIS® Registry|Electronic Health Records and Registries|Information on Data Sources|Vision & Eye Health Surveillance System|Vision Health Initiative (VHI)|CDC [Internet]. 2019 [cited 2021 May 19]. Available from https://www.cdc.gov/visionhealth/ vehss/data/ehr-registries/iris.html
S. Khanna and D. S. Chang 11. Al-Bahlal A, Khandekar R, Al Rubaie K, Alzahim T, Edward DP, Kozak I. Changing epidemiology of neovascular glaucoma from 2002 to 2012 at King Khaled Eye Specialist Hospital. Saudi Arabia Indian J Ophthalmol. 2017;65(10):969–73. 12. Rodrigues GB, Abe RY, Zangalli C, Sodre SL, Donini FA, Costa DC, et al. Neovascular glaucoma: a review. Int J Retina Vitreous. 2016;2(1):26. 13. Yu X, Sun X, Guo W. The etiologic considerations of neovascular glaucoma. Chin J Ophthalmol Otorhinolaryngol. 2004;5:291–3. 14. Brown GC, Magargal LE, Schachat A, Shah H. Neovascular glaucoma: etiologic considerations. Ophthalmology. 1984;91(4):315–20. 15. Al-Shamsi HN, Dueker DK, Nowilaty SR, Al-Shahwan SA. Neovascular glaucoma at king khaled eye specialist hospital—etiologic considerations. Middle East Afr J Ophthalmol. 2009;16(1):15–9. 16. Woodcock MGL, Richards JC, Murray ADN. The last 11 years of Molteno implantation at the University of Cape Town. Refining our indications and surgical technique. Eye. 2008;22(1):18–25. 17. Liu L, Xu Y, Huang Z, Wang X. Intravitreal ranibizumab injection combined trabeculectomy versus Ahmed valve surgery in the treatment of neovascular glaucoma: assessment of efficacy and complications. BMC Ophthalmol [Internet]. 2016 May 26 [cited 2021 Apr 25];16. Available from https://www.ncbi. nlm.nih.gov/pmc/articles/PMC4882850/ 18. Lazcano-Gomez G, Soohoo JR, Lynch A, Bonell LN, Martinez K, Turati M, et al. Neovascular glaucoma: a retrospective review from a tertiary eye care center in Mexico. J Curr Glaucoma Pract. 2017;11(2):48–51. 19. Rong AJ, Swaminathan SS, Vanner EA, Parrish RK. Predictors of neovascular glaucoma in central retinal vein occlusion. Am J Ophthalmol. 2019;204:62–9. 20. Goto A, Inatani M, Inoue T, Awai-Kasaoka N, Takihara Y, Ito Y, et al. Frequency and risk factors for neovascular glaucoma after vitrectomy in eyes with proliferative diabetic retinopathy. J Glaucoma. 2013;22(7):572–6. 21. Oh SA, Ra H, Jee D. Socioeconomic status and glaucoma: associations in high levels of income and education. Curr Eye Res. 2019;44(4):436–41. 22. Raj S, Savla LP, Thattaruthody F, Seth NG, Kaushik S, Pandav SS. Predictors of visual impairment in primary and secondary glaucoma in a tertiary institute in North India. Eur J Ophthalmol. 2020;30(1):175–80. 23. Hayreh SS. Neovascular glaucoma. Prog Retin Eye Res. 2007;26(5):470–85. 24. Senthil S, Dada T, Das T, Kaushik S, Puthuran GV, Philip R, et al. Neovascular glaucoma—a review. Indian J Ophthalmol. 2021;69(3):525–34. 25. Barac IR, Pop MD, Gheorghe AI, Taban C. Neovascular secondary glaucoma, etiology and pathogenesis. Rom J Ophthalmol. 2015;59(1):24–8. 26. Sivak-Callcott JA, O’Day DM, Gass JDM, Tsai JC. Evidence-based recommendations for the diagnosis and treatment of neovascular glaucoma1 1The
Epidemiology of Neovascular Glaucoma authors do not have any proprietary or financial interest in any products or devices discussed in this study. Ophthalmology. 2001;108(10):1767–76. 27. Lee P, Wang CC, Adamis AP. Ocular neovascularization: an epidemiologic review. Surv Ophthalmol. 1998;43(3):245–69. 28. Preda M, Davidescu L, Damian C, Irimia A, Sollosy M. Neovascular glaucoma—prevention. Oftalmologia. 2006;50(2):108–14. 29. Hamard P, Baudouin C. Consensus on neovascular glaucoma. J Fr Ophtalmol. 2000;23(3):289–94. 30. Lee JH, Kim EY, Kim TK, Shin HY, Kim SY, Lee YC, et al. Prognostic factors of neovascular glaucoma in eyes with treated proliferative diabetic retinopathy. J Korean Ophthalmol Soc. 2017;58(4):415–9. 31. Havens SJ, Gulati V. Neovascular Glaucoma. Dev Ophthalmol. 2016;55:196–204. 32. Ohrt V. The frequency of rubeosis iridis in diabetic patients. Acta Ophthalmol. 1971;49(2):301–7. 33. A randomized clinical trial of early panretinal photocoagulation for ischemic central vein occlusion
9 The Central Vein Occlusion Study Group N Report. Ophthalmology. 1995;102(10):1434–44. 34. Natural history and clinical management of central retinal vein occlusion. The Central Vein Occlusion Study Group. Arch Ophthalmol. 1997;115(4):486–91. 35. Chen H-F, Chen M-C, Lai C-C, Yeung L, Wang N-K, Chen HS-L, et al. Neovascular glaucoma after central retinal vein occlusion in pre-existing glaucoma. BMC Ophthalmol [Internet] 2014 Oct 5 [cited 2021 Apr 25];14. Available from https://www.ncbi.nlm.nih. gov/pmc/articles/PMC4193090/ 36. Yang H, Yu X, Sun X. Neovascular glaucoma: handling in the future. Taiwan J Ophthalmol. 2018;8(2):60–6. 37. Terelak-Borys B, Skonieczna K, Grabska-Liberek I. Ocular ischemic syndrome—a systematic review. Med Sci Monit. 2012;18(8):RA138–44. 38. Kim YH, Sung MS, Park SW. Clinical features of ocular ischemic syndrome and risk factors for neovascular glaucoma. Korean J Ophthalmol. 2017;31(4):343–50.
Pathophysiology of Neovascular Glaucoma Qing Wang and Thomas V. Johnson
Neovascular glaucoma (NVG) is a particularly aggressive form of secondary glaucoma that tends to present acutely when patients develop abrupt elevations of intraocular pressure (IOP). NVG is characterized by neovascularization of the anterior segment, fibrovascular proliferation within an initially open anterior chamber angle, and eventual synechial angle closure. Ocular hypertension leads to retinal ganglion cell injury and death, with the characteristic optic nerve head cupping and progressive visual field defects common to all forms of glaucomatous optic neuropathy. Whereas the term neovascular glaucoma was coined in 1963 by Weiss and colleagues [1], its manifestations and associations with retinal vascular disease have been recognized since the second half of the nineteenth century [2]. Nonetheless, NVG remains a visually devastating entity that is challenging to treat and frequently resistant to medical therapy alone. As such, early recognition and treatment of the ocular pathologies that predispose to NVG are critical for minimizing visual morbidity. A clear understanding of the mechanisms that drive anterior segment neovascularization is essential for effective treatment of the disease and for future
Q. Wang · T. V. Johnson (*) Glaucoma Center of Excellence, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA e-mail: [email protected]
development of increasingly effective anti-neovascular therapies. In this chapter, we will describe the natural history of, discuss ocular conditions that predispose to, and review the molecular and cellular mechanisms underlying anterior segment neovascularization.
1 Clinical Aspects of Anterior Segment Neovascularization The iris, as a uveal tissue, is highly vascularized. Ophthalmologists who perform laser iridotomy learn to recognize (and avoid) physiologic iris vessels, which are typically oriented radially and contained within stromal tissue giving them a gray appearance when not covered by pigmented epithelium (Fig. 1b). Physiologic iris vessels possess endothelial cells bound by tight junctions (zonulae occludentes) without fenestrations, thereby maintaining the blood-aqueous barrier. In contrast, iris neovascularization, or rubeosis, is characterized by the presence of abnormal neovessels, which tend to grow in disorganized, meandering trajectories and are most easily visible at the pupil margin (Fig. 1c–d). They are bright red in appearance, and their endothelial cells contain fenestrations leading to increased permeability, which sometimes manifests as anterior chamber flare on slit-lamp examination. Fluorescein iris angiography demonstrates leakage from neovessels [3]. Neovessels are often
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 M. Qiu (ed.), Neovascular Glaucoma, Essentials in Ophthalmology, https://doi.org/10.1007/978-3-031-11720-6_3
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Fig. 1 (a) Ischemic retina in the setting of a superior hemiretinal vein occlusion produces vasoproliferative ligands including vascular endothelial growth factor (green dots). These factors diffuse in a gradient toward the anterior segment, enter the aqueous fluid through the posterior chamber, flow through the pupil into anterior chamber, and finally exit the eye through the trabecular meshwork. Inserts (b–d) show a magnified view of the iridocorneal angle. (b) Normal, physiologic iris vessels (IV) are radially oriented and contained within stromal
tissue. The angle is open with a clear distinction between pigmented trabecular meshwork (TM) and scleral spur (SS). (c) Iris neovessels (NV) grow in disorganized, meandering trajectories and can be seen at the pupil margin and extending within a fibrovascular membrane into the angle. (d) Contraction of the fibrovascular membrane in late neovascularization leads to synechial closure of the angle, as seen by peripheral anterior synechiae (PAS) that sequester the TM. Artwork by Kevin Y Zhang, BS, Wilmer Eye Institute, Johns Hopkins University
accompanied by myofibroblasts, giving rise to a “fibrovascular membrane” that can appear shiny or gray on the iris surface [4]. In some circumstances, fibrovascular membranes can form posterior synechiae to the crystalline lens, or even a posterior chamber intraocular lens, leading to iris bombe. Neovessels are fragile and bleed relatively easily, which can lead to development of hyphema following rapid IOP lowering, as in the context of anterior chamber paracentesis or aqueous shunt implantation. IOP elevation occurs when neovascularization of the iris begins to extend into the anterior chamber angle. At early stages, the angle remains open and pigmented trabecular meshwork is visible on gonioscopy, though neovessels are visible within
the angle (Figs. 1c and 2a, b). Sometimes discrete vessels are difficult to ascertain but the meshwork itself develops a pink or red hue. Eventually fibrovascular proliferation and tissue contraction cause development of adhesions between the iris and the angle tissue, termed peripheral anterior synechiae (PAS). Without intervention to suppress the underlying neovascular drive, PAS lead to widespread synechial angle closure (Figs. 1d and 2a, b). If neovascularization of the angle is recognized prior to extensive synechial closure, prompt treatment is sometimes successful in achieving regression of neovessels and normalization of IOP [5]. Therefore, the importance of gonioscopy in the clinical evaluation of at-risk patients cannot be overemphasized.
Pathophysiology of Neovascular Glaucoma
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Fig. 2 (a) Angle closure due to peripheral anterior synechiae, with red arrow designating the scleral spur and dotted red oval outlining the region of the trabecular meshwork and Schlemm’s canal. (b) Higher magnification view of the region outlined by the green rectangle in (a) shows newly formed thin-walled vessels on the iris surface that are adherent to the sclera (red arrows), and thick-walled vessels in the iris stroma (asterisks). (c) Severe retinal ganglion cell loss is present, as well as
astrocytic gliosis in the retinal nerve fiber layer (red arrows). (d) Severe cupping of the optic nerve head (asterisk), with posterior bowing of the lamina cribrosa. Separation of the peripapillary neural retina from RPE is artifactual. Histology courtesy of Charles G Eberhart, MD, PhD, Director of Neuropathology and Ophthalmic Pathology, Wilmer Eye Institute, Johns Hopkins University
2 Cell Biology of Anterior Segment Neovascularization
ducing a vascular sprout [10]. Finally, phalanx cells follow stalk cells to line the inner lumen of the new vessel [11]. Pericytes and stromal cells play supportive roles in neovascularization. Landmark work in cynomolgus monkeys in the late 1980s provided detailed histologic data regarding the cellular events that occur during anterior segment neovascularization [12]. Within 5 days of retinal vein occlusion, tritiated thymidine uptake was significant within vascular endothelial cells, showing increased cellular proliferation. By 4 weeks, thickened vascular membranes formed on the anterior iris surface, with anterior traction at the pupil causing
Neovessels arise from existing vascular networks through a hierarchical activation of endothelial cells termed sprouting angiogenesis [6, 7], a phenomenon that occurs in both physiologic states, such as development and wound healing, and during pathologic neovascularization including in tumors [8]. In response to vasoproliferative signaling ligands, endothelial tip cells extend filopodia away from existing capillary walls [9]. Secondary endothelial stalk cells then follow tip cells to generate a vascular lumen thereby pro-
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Fig. 3 (a) This anterior segment slit-lamp photograph shows prominent iris neovascularization, and fibrovascular traction at the pupil margin has caused ectropion uveae. (b) En-face OCT angiography demonstrates flow within these abnormal iris vessels. (c) Cross-sectional OCT angiography demonstrates flow (red) through the fibrovascular membrane that is superficial to the iris
stroma. The red box in (a) corresponds to the yellow box in (b). Reprinted from: Lee WD, Devarajan K, Chua J, et al., Optical coherence tomography angiography for the anterior segment. Eye and Vision. 6, 4 (2019). https://doi. org/10.1186/s40662-019-0129-2 under open access CC BY 4.0 License (https://creativecommons.org/licenses/ by/4.0/legalcode)
e ctropion uveae. At this point, cellular proliferation was primarily seen in iris stromal cells which had discarded their typical intercellular associations with iris melanocytes, adopted a myofibroblast phenotype, and migrated anteriorly to constitute the neovascular membrane. These findings reinforce the idea that NVG is characterized not just by abnormal blood vessels, but rather by a contractile fibrovascular membrane complex (Fig. 3).
typically, though not exclusively, occurring with the proliferative form of the disease; retinal venous occlusion, responsible for another third of NVG and often manifesting 60–90 days after the onset of venous occlusion; and ocular ischemic syndrome (i.e., carotid artery occlusive disease). The degree of retinal ischemia correlates with the risk for anterior segment neovascularization and NVG, as reflected in the increased risk in ischemic over nonischemic central retinal vein occlusion (CRVO) and in CRVO over hemiretinal vein occlusion [13]. Ocular ischemic syndrome manifests with global limitations of ocular blood flow and therefore anterior segment ischemia also contributes to the development of NVG in this condition. Other rarer conditions also contribute to retinal ischemia and can predispose to NVG including radiation, ocular malignancy, chronic uveitis, retinal vasculitis, and chronic retinal detachment. Because intraocular blood flow is proportional to the difference between mean arterial pressure and IOP, the ocular hypertension resulting from NVG exacerbates retinal ischemia, which in turn, hastens the drive for further
3 Posterior Segment Ischemia Anterior segment neovascularization and fibrovascular proliferation are driven by proangiogenic molecular ligands that diffuse forward from the posterior segment (Fig. 1a). Vascular growth factors are produced by the retina in response to hypoxia, and therefore the ocular conditions that most commonly predispose to NVG are the most frequently occurring retinal vascular diseases: diabetic retinopathy, responsible for approximately one-third NVG cases and
Pathophysiology of Neovascular Glaucoma
anterior segment neovascularization. This positive feedback loop between retinal ischemia and NVG at least partially explains the frequently poor visual outcomes in patients with the disease.
4 Vasoproliferative Factors The presence of a retina-derived vasoproliferative factor that drives neovascularization in the setting of retinal ischemia was first proposed by Michaelson in 1948 [14]. Candidates vetted in the ensuing hunt for such a growth factor included insulin-like growth factors, fibroblast growth factors, and growth hormone, amongst others. None appeared to serve as a definitive link between retinal ischemic disease and neovascularization until vascular endothelial growth factor (VEGF) emerged [15].
4.1 Vascular Endothelial Growth Factor First described by Judah Folkman and colleagues in 1970 as a tumor-derived angiogenic factor [16] and purified by Napoleone Ferrara and William Henzel in 1989 [17], VEGF is actually a family of five growth factors composed of VEGFs A-D and placental growth factor. Among the family members, VEGF-A is the most relevant to ischemic ocular disease. VEGF-A is produced in response to hypoxia, under transcriptional regulation of hypoxia-inducible factor (HIF)-1α. Müller glia, retinal pigment epithelial cells, capillary endothelial cell and pericytes, and some retinal neurons all produce VEGF [18, 19]. Whereas VEGF is undetectable in the aqueous humor of normal eyes, its diffusion through the vitreous in pathologic states exposes anterior segment tissues to the growth factor (Fig. 1a). VEGF signal transduction is complex, owing to alternative splicing of transcripts, with VEGF165 being the most potent for driving neovascularization. In addition, the dimeric tyrosine kinase VEGF receptors form complexes with numerous other cell surface receptors, thereby altering their sig-
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naling function. VEGFR2 is the receptor most relevant for endothelial cell signaling and neovascularization. Within vascular endothelial cells, VEGF simulates proliferation, antiapoptotic signaling, migration, and increased permeability through multiple pathways, including RAS/RAF/ERK/MAPK, PI3K-PBK/AKT, and PLC-𝛾 /Ca++/eNOS [20, 21]. The centrality of VEGF to NVG pathogenesis is supported by especially high growth factor concentrations in the aqueous humor of patients with active iris neovascularization in the setting of diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity [22]. Indeed, VEGF levels in the aqueous humor of NVG patients are more than 40-fold higher than in patients with primary open angle glaucoma [23]. VEGF is sufficient to cause iris neovascularization, as demonstrated in nonhuman primate models following intravitreal VEGF injection [24]. Prolonged exposure to VEGF over 30 days further induces NVG with IOP elevation and the characteristic anatomical changes described above. The requirement of VEGF in developing NVG was established in primate models with laser-induced retinal venous occlusion, where anti-VEGF antibodies blocked iris neovascularization development [25]. This finding heralded the success of anti-VEGF treatment in treating not only posterior segment disease in retinal ischemic disorders but also early stages of NVG. The beneficial effects of panretinal photocoagulation (PRP) in reducing iris and angle neovascularization and NVG are well established [26]. In support of VEGF as a mediator of NVG pathogenesis, aqueous VEGF levels are reduced in patients with diabetic retinopathy following PRP treatment in a dose-dependent manner [27]. The therapeutic targeting of VEGF has revolutionized ophthalmology by providing new avenues for treating ocular disease, and NVG is no exception. The first FDA-approved pharmacologic VEGF inhibitor pegaptanib (Macugen®) was a pegylated aptamer (an oligonucleotide) designed specifically to bind and sequester VEGF-A. Subsequently, a series of monoclonal antibodies and antibody-receptor hybrids that
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recognize and sequester VEGF-A have been developed for the treatment of diabetic retinopathy and age-related macular degeneration, though they are frequently used for other ischemic retinal conditions as well. This has provided data in human patients that corroborate the central role of VEGF in driving NVG pathogenesis. Both intracameral and intravitreal injection of bevacizumab lead to rapid reduction in vascular leakage and regression of iris neovascularization within 48 hours in early disease, and, more importantly, IOP reduction when the angle remains open [3, 5, 28–32]. This is associated with a direct reduction in aqueous VEGF levels [33]. However, in late-stage disease when the angle has already become partially or fully synechially closed, intravitreal bevacizumab is generally not sufficient in achieving adequate IOP control [5]. This observation underscores the critical importance of early diagnosis of NVG. Since intravitreal antibody has a half-life on the order of days, anti-VEGF therapy induces temporary regression of neovascularization and repeated treatment is needed to prevent recurrence of neovascularization. Interestingly, anterior segment angiography shows that while bevacizumab reduces the intense vascular leakage seen with iris and iridocorneal angle neovessels, it does not change the overall vascular structure of the anterior segment, suggesting that these vessels may not fully regress [3, 28]. Ultimately, PRP leads to structural reduction of neovessels in the anterior segment [34] and a more permanent reduction of VEGF signaling by suppressing growth factor production. Moreover, other proangiogenic factors play a role in retinal neovascularization that are not targeted by VEGF-binding antibodies (see below). While evidence for these other factors playing a direct role in anterior segment neovascularization is less readily available, they may explain observations of persistent anterior and/ or posterior segment fibrovascular activity in the face of ongoing anti-VEGF treatment. Therefore, while anti-VEGF therapy is useful to induce
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short-term anterior segment regression of neovascularization, many clinicians recommend that PRP be a component of the treatment repertoire for NVG [35].
4.2 Platelet-Derived Growth Factor (PDGF) The platelet-derived growth factors are another family of signaling ligands that regulate cell proliferation and growth, particularly in vasculature and other mesenchymal-derived tissues [36]. PDGF exists as a homo- or heterodimer of four subunits, PDGFs-A-D, acting through two monomeric tyrosine kinase receptors, PDGFR-α and -β. In ocular tissue, PDGF proteins are closely associated with pericytes and the maintenance of the retinal microvasculature. While PDGF expression is increased in retinal hypoxia, their effects are thought to be distinct from and complimentary to VEGF signaling in endothelial cells. PDGF-BB, for example, protects retinal microvasculature from damage caused by metabolic inhibitors [37]. However, in mouse studies, upregulation of retinal PDGF-BB also leads to neovascular proliferation in the posterior segment [38], whereas blockage of PDGF-BB signaling reduces the development of choroidal neovascularization at breaks in Bruch’s membrane [39]. Other PDGF family members, particularly PDGF-C and -D have been shown to play a role in ischemia-induced retinopathy [36]. Whereas PDGF has been implicated strongly in AMD, its role in the pathophysiology of NVG is less clear. Expression of PDGF-C is upregulated in aqueous humor of patients with NVG [40]. Moreover, PDGF levels are high in patients with NVG even after treatment with bevacizumab, suggesting that PDGF regulation may be VEGF- independent [41]. Whereas combination therapies targeting VEGF and PDGF are of clinical interest and could potentially be useful in NVG, PDGF inhibitors are not approved for the treatment of ocular disease. Significant interest in
Pathophysiology of Neovascular Glaucoma
PDGF and other vasoactive targets exist for the treatment of AMD and diabetic retinopathy [42, 43]; however, the failures in 2016 of two phase-3 randomized clinical trials for the anti-PDGF therapy, pegpleranib (Fovista), have unfortunately stalled further development in this arena for the time being [44, 45].
4.3 Other Angiogenic Factors Angiopoietin-like 4 (ANGPTL4) has emerged as another hypoxia-induced vasoproliferative factor. The aqueous fluid of patients with proliferative diabetic retinopathy recently treated with anti- VEGF is capable of experimentally inducing endothelial tubule formation in vitro, suggesting that there are other factors that contribute to neovascularization. In an expression screen of retinal Müller cells subjected to hypoxia, ANGPTL4 was identified as being upregulated at levels similar to VEGF [46]. Moreover, ANGPTL4 was also upregulated in the vitreous and aqueous fluid of patients with PDR. Neutralizing antibodies against ANGPTL4 inhibited the in vitro angiogenic potential of aqueous fluid from these patients and was additive with the effects of anti- VEGF. Interestingly, aqueous ANGPTL4 is elevated in BRVO patients with macular edema and correlates with retinal nonperfusion area [47]. Like VEGF, interleukin (IL)-6 (IL-6) is induced by hypoxia. Elevated levels of IL-6 are found in the aqueous humor of patients with CRVO only when anterior segment neovascularization is evident [48]. Erythropoietin is a HIF-1α-regulated glycoprotein that is elevated in the vitreous of patients with PDR. In murine models, blockage of erythropoietin has been shown to decrease retinal neovascularization in vivo and inhibit endothelial cell proliferation in in vitro assays [49]. Other proangiogenic or profibrotic factors that may play a role in anterior segment neovascularization include: transforming growth factor (TGF)-β [50], fibroblast growth factor (FGF) [51], and tumor necrosis factor (TNF)-α [52].
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These proangiogenic factors act in balance with antiangiogenic signaling molecules, chief among them being pigment epithelium-derived factor (PEDF) [53, 54]. Indeed, not only are proangiogenic factors produced in retinal ischemic disease, but also PEDF levels decline [55–58], due to hypoxia-induced matrix metalloprotease degradation, further tipping the molecular signaling balance toward neovascularization [59, 60]. PEDF functions by regulating cell cycle progression and apoptosis through Fas, p38 MAPK, and p53 signaling [61–63].
5 From Retina to Aqueous As vasoproliferative growth factors are primarily produced by tissues of the posterior segment, it follows that diffusion from the vitreous cavity exposes anterior segment tissues to VEGF and other vasogenic growth factors. Indeed, a common route of molecular clearance from the vitreous is through anterior diffusion into the aqueous of the posterior then anterior chamber and subsequent clearance through the trabecular meshwork (Fig. 1a) [64]. A concentration gradient of VEGF has been shown in eyes with diabetic macular edema with highest levels within the posterior premacular vitreous and lowest levels within the anterior peripheral vitreous [65]. In support of that mechanism, neovascularization is first visible at the pupil margin where the highest flux of aqueous humor occurs. One might speculate that diffusion rates of vasoproliferative factors to the front of the eye, and hence the incidence of NVG, would therefore be altered by vitrectomy. VEGF clearance from the vitreous cavity indeed increases after vitrectomy in rabbit eyes [66]. In reality, confounding factors such as severity of retinal disease leading to complications that necessitate vitrectomy (vitreous hemorrhage or traction retinal detachment) hamper the ability to test this hypothesis clinically. However, it has been noted in multiple studies that the likelihood of developing NVG after vitrectomy is greater in
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aphakic or pseudophakic eyes, than in phakic eyes [67–70], suggesting that the crystalline lens may serve as a barrier to diffusion of vasoproliferative ligands to the front of the eye.
6 Beyond Retinal Ischemia Despite the focus on the retina as the source of proangiogenic signals, recent investigations have turned toward the anterior segment as a potential secondary source of VEGF. Anterior segment ischemia, induced by cauterization of the long posterior ciliary arteries, induces VEGF production by the ciliary body and anterior segment neovascularization in rabbits [71]. Indeed, immunocytochemistry and in situ hybridization studies have confirmed the nonpigmented ciliary epithelium as a site of VEGF synthesis in NVG [72]. This observation is interesting in the context of patients whose NVG is refractory to PRP and may be particularly relevant in conditions where anterior segment ischemia is a prominent feature, such as OIS. A better understanding of the effects of neovascularization on the ciliary body may also help shed light on why rates of hypotony following cyclophotocoagulation are higher in patients with NVG than with other forms of glaucoma [73].
7 Conclusions NVG results from posterior segment vasoproliferative signals in the setting of retinal ischemia, leading to anterior segment neovascularization. A mechanistic understanding of proangiogenic growth factor signaling has brought us into the anti-VEGF era of ophthalmology. Other potential treatments are on the horizon that will target anterior segment vasoproliferation in early disease and potentially circumvent NVG development. There is, however, still a role for more traditional treatments, such as PRP, for more sustained control of vasoproliferative signals, and for surgical treatments in the setting of secondary synechial angle closure in chronic NVG.
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20 44. Dunn EN, Hariprasad SM, Sheth VS. An overview of the Fovista and Rinucumab trials and the fate of anti- PDGF medications. Ophthalmic Surg Lasers Imaging Retina. 2017;48:100–4. 45. Hussain RM, Ciulla TA. Emerging vascular endothelial growth factor antagonists to treat neovascular age-related macular degeneration. Expert Opin Emerg Drugs. 2017;22:235–46. 46. Babapoor-Farrokhran S, Jee K, Puchner B, et al. Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy. Proc Natl Acad Sci. 2015;112:E3030–9. 47. Kim JH, Shin JP, Kim IT, Park DH. Aqueous angiopoietin-like 4 levels correlate with nonperfusion area and macular edema in branch retinal vein occlusion. Invest Ophthalmol Vis Sci. 2016;57:6–11. 48. Chen KH, Wu CC, Roy S, Lee SM, Liu JH. Increased interleukin-6 in aqueous humor of neovascular glaucoma. Invest Ophthalmol Vis Sci. 1999;40:2627–32. 49. Watanabe D, Suzuma K, Matsui S, et al. Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy. New Engl J Med. 2005;353:782–92. 50. Yu X-B, Sun X-H, Dahan E, Guo W-Y, Qian S-H, Meng F-R, Song Y-L, Simon GJB. Increased levels of transforming growth factor-beta1 and -beta2 in the aqueous humor of patients with neovascular glaucoma. Ophthalmic Surg Lasers Imaging. 2007;38:6–14. 51. Tripathi RC, Borisuth NSC, Tripathi BJ. Detection, quantification, and significance of basic fibroblast growth factor in the aqueous humor of man, cat, dog and pig. Exp Eye Res. 1992;54:447–54. 52. Gardiner TA, Gibson DS, de Gooyer TE, de la Cruz VF, McDonald DM, Stitt AW. Inhibition of tumor necrosis factor-α improves physiological angiogenesis and reduces pathological neovascularization in ischemic retinopathy. Am J Pathol. 2005;166:637–44. 53. Gao G, Li Y, Zhang D, Gee S, Crosson C, Ma J. Unbalanced expression of VEGF and PEDF in ischemia- induced retinal neovascularization. FEBS Lett. 2001;489:270–6. 54. Ogata N, Nishikawa M, Nishimura T, Mitsuma Y, Matsumura M. Unbalanced vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor in diabetic retinopathy. Am J Ophthalmol. 2002;134:348–53. 55. Ogata N, Nishikawa M, Nishimura T, Mitsuma Y, Matsumura M. Inverse levels of pigment epithelium- derived factor and vascular endothelial growth factor in the vitreous of eyes with rhegmatogenous retinal detachment and proliferative vitreoretinopathy. Am J Ophthalmol. 2002;133:851–2. 56. Spranger J, Osterhoff M, Reimann M, et al. Loss of the antiangiogenic pigment epithelium-derived factor in patients with angiogenic eye disease. Diabetes. 2001;50:2641–5. 57. Ogata N, Tombran-Tink J, Nishikawa M, Nishimura T, Mitsuma Y, Sakamoto T, Matsumura M. Pigment epithelium-derived factor in the vitreous is low in dia-
Q. Wang and T. V. Johnson betic retinopathy and high in rhegmatogenous retinal detachment. Am J Ophthalmol. 2001;132:378–82. 58. Holekamp NM, Bouck N, Volpert O. Pigment epithelium-derived factor is deficient in the vitreous of patients with choroidal neovascularization due to age-related macular degeneration11InternetAdvance publication at ajo.com. May 7, 2002. Am J Ophthalmol. 2002;134:220–7. 59. Gao G, Li Y, Gee S, Dudley A, Fant J, Crosson C, Ma J. Down-regulation of vascular endothelial growth factor and up-regulation of pigment epithelium- derived factor: a possible mechanism for the anti- angiogenic activity of plasminogen kringle 5*. J Biol Chem. 2002;277:9492–7. 60. Notari L, Miller A, Martínez A, Amaral J, Ju M, Robinson G, Smith LEH, Becerra SP. Pigment epithelium–derived factor is a substrate for matrix metalloproteinase type 2 and type 9: implications for downregulation in hypoxia. Invest Ophthalmol Vis Sci. 2005;46:2736–47. 61. Volpert OV, Zaichuk T, Zhou W, Reiher F, Ferguson TA, Stuart PM, Amin M, Bouck NP. Inducer- stimulated Fas targets activated endothelium for destruction by anti-angiogenic thrombospondin-1 and pigment epithelium–derived factor. Nat Med. 2002;8:349–57. 62. Chen L, Zhang SS-M, Barnstable CJ, Tombran-Tink J. PEDF induces apoptosis in human endothelial cells by activating p38 MAP kinase-dependent cleavage of multiple caspases. Biochem Bioph Res Commun. 2006;348:1288–95. 63. Ho T-C, Chen S-L, Yang Y-C, Liao C-L, Cheng H-C, Tsao Y-P. PEDF induces p53-mediated apoptosis through PPAR gamma signaling in human umbilical vein endothelial cells. Cardiovasc Res. 2007;76:213–23. 64. del Amo EM, Rimpelä A-K, Heikkinen E, et al. Pharmacokinetic aspects of retinal drug delivery. Prog Retin Eye Res. 2017;57:134–85. 65. Shimada H, Akaza E, Yuzawa M, Kawashima M. Concentration gradient of vascular endothelial growth factor in the vitreous of eyes with diabetic macular edema. Invest Ophthalmol Vis Sci. 2009;50:2953–5. 66. Lee SS, Ghosn C, Yu Z, et al. Vitreous VEGF clearance is increased after vitrectomy. Invest Ophthalmol Vis Sci. 2010;51:2135–8. 67. Aaberg TM. Clinical results in vitrectomy for diabetic traction retinal detachment. Am J Ophthalmol. 1979;88:246–53. 68. Summanen P. Neovascular glaucoma following vitrectomy for diabetic eye disease. Acta Ophthalmol. 1988;66:110–6. 69. Blankenship GW. The lens Influence on diabetic vitrectomy results: report of a prospective randomized study. Arch Ophthalmol. 1980;98:2196–8. 70. Rice TA, Michels RG, Rice EF. Vitrectomy for diabetic traction retinal detachment involving the macula. Am J Ophthalmol. 1983;95:22–33.
Pathophysiology of Neovascular Glaucoma 71. Tawara A, Kubota T, Hata Y, Sakamoto T, Honda M, Yoshikawa H, Inomata H, Ohnishi Y. Neovascularization in the anterior segment of the rabbit eye by experimental anterior ischemia. Graefes Arch Clin Exp Ophthalmol. 2002;240:144–53. 72. Chalam KV, Brar VS, Murthy RK. Human ciliary epithelium as a source of synthesis and secretion of
21 vascular endothelial growth factor in neovascular glaucoma. JAMA Ophthalmol. 2014;132:1350–4. 73. Ramli N, Htoon HM, Ho CL, Aung T, Perera S. Risk factors for hypotony after transscleral diode cyclophotocoagulation. J Glaucoma. 2012;21:169–73.
Clinical Diagnosis of Neovascular Glaucoma in the Ophthalmology Office Inas F. Aboobakar and Michael M. Lin
1 Introduction
rior segment neovascularization, but there is no visible neovascularization of the iris (NVI) or Neovascular glaucoma (NVG) is a particularly angle (NVA) and the IOP is normal; this has aggressive type of secondary glaucoma that classically been termed the prerubeosis stage. develops in the setting of retinal ischemia and As the disease progresses, there is visible NVI subsequent release of angiogenic factors into the and/or NVA, but the intraocular pressure (IOP) aqueous humor [1]. The most common underly- is still normal and the patient is asymptomatic; ing etiologies for NVG are proliferative diabetic this has classically been termed the preglauretinopathy (PDR), central retinal vein occlusion coma stage. As the NVA progresses, the devel(CRVO), and ocular ischemic syndrome (OIS). opment of a fibrovascular membrane in the PDR and CRVO each comprise approximately angle obstructs aqueous outflow and the IOP one-third of NVG cases, and OIS is the most becomes elevated, though there is no synechial common etiology amongst the remaining one- angle closure yet; this has classically been third of cases [2]. Other rarer causes include vari- termed the open-angle glaucoma stage. As the ous ocular tumors (e.g., retinoblastoma, uveal fibrovascular tissue in the angle contracts to melanomas, ciliary body medulloepithelioma, form peripheral anterior synechiae, there is proand vasoproliferative tumors of the retina), cen- gressive synechial angle closure and profoundly tral retinal artery occlusion, sickle cell retinopa- elevated IOP; this has classically been termed thy, radiation retinopathy, carotid-cavernous the closed-angle glaucoma stage. Of note, the fistulas, and ocular inflammatory disease [3–8]. classical terms “open-angle NVG” and “closedSystemic conditions that have been associated angle NVG” refer to anterior segment neovaswith the development of neovascular glaucoma cularization with elevated IOP with or without include juvenile xanthogranuloma, systemic true glaucomatous optic neuropathy. However, lupus erythematosus, cryoglobulinemia, and neu- the historical convention is to refer to these rofibromatosis type I [9–13]. stages as “NVG,” so for the purpose of this The earliest stage on the NVG spectrum is chapter, this terminology will be used. Future when an eye is at high risk for developing ante- consensus panels are needed to determine whether neovascular “ocular hypertension” may be a more descriptive term in the setting of elevated IOP without true glaucomatous optic I. F. Aboobakar · M. M. Lin (*) Massachusetts Eye and Ear, Harvard Medical School, neuropathy. Boston, MA, USA e-mail: [email protected]
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 M. Qiu (ed.), Neovascular Glaucoma, Essentials in Ophthalmology, https://doi.org/10.1007/978-3-031-11720-6_4
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In this chapter, we discuss the clinical evaluation of patients who are at high risk of developing NVG and the diagnosis of NVG in the outpatient clinic setting, including critical components of the patient history, physical examination, and ancillary testing.
2 Clinical History A thorough systemic and medical history is critical to identify possible etiologies for the development of NVG. This includes assessing for vascular risk factors (diabetes, hypertension, hyperlipidemia, coronary artery disease, cerebrovascular accident, and carotid occlusive disease), coagulopathies, and vasculitides. The patient’s past ocular history may reveal possible conditions that can lead to the development of NVG, including PDR or CRVO. It is important to assess what previous treatments the patient has had for underlying retinal ischemic disorders (e.g., panretinal photocoagulation or anti-VEGF injections) and whether the patient has ever been diagnosed with high IOP or glaucoma in the past. It is also critical to assess the patient’s symptoms as well as their onset and duration. History of sudden onset vision loss a few months prior to presentation may raise CRVO higher on the differential, while episodes of transient vision loss (amaurosis fugax) may suggest ocular ischemic syndrome as an underlying etiology. In the early stages of NVG, patients may be asymptomatic. Conversely, patients who present in the angle- closure stage with acute elevations in IOP typically have associated eye pain, decreased vision, headaches, nausea/vomiting, and halos around lights. Hemodialysis may acutely increase IOP and lead to intermittent pain or blurry vision during dialysis sessions.
3 Examination The diagnosis of NVG is mainly clinical, and a complete ophthalmologic examination is therefore critical. A special challenge in examination is that while many patients with PDR, CRVO,
I. F. Aboobakar and M. M. Lin
and other NVG-predisposing conditions are managed by retina specialists who typically examine eyes after dilation, key parts of the examination such as evaluating for NVI are best performed before dilation. Moreover, retina specialists may not be as likely to perform or be comfortable with gonioscopy as glaucoma specialists. Many patients with early NVG are asymptomatic, and their disease may only be detected if an astute clinician was performing routine screening gonioscopy on high-risk patients. Important components of the examination for eyes at risk of NVG or with NVG are highlighted below.
3.1 Visual Acuity It is critical to check visual acuity at every clinic visit and to compare to the baseline. Patients with NVG often have poor visual acuity due to corneal edema in the setting of acutely elevated IOP, underlying retinal pathology (e.g., vitreous hemorrhage, macular edema, macular ischemia), or glaucomatous optic neuropathy. However, visual acuity can range widely in all stages of NVG, with some patients with closed-angle NVG maintaining 20/20 central vision after IOP is stabilized and underlying retinal disease is treated.
3.2 Pupil Examination The pupils should be assessed for a relative afferent pupillary defect (RAPD), as this can be a sign of asymmetric optic nerve damage. In patients with CRVO, studies have demonstrated that patients with an RAPD are at increased risk for developing NVI [14]. However, the presence of an RAPD does not necessarily indicate glaucomatous optic neuropathy, as the underlying retinal disease such as CRVO could cause RAPD even in the absence of NVG.
3.3 Intraocular Pressure (IOP) In the earliest stages of the disease process, the IOP may still be normal even though there is vis-
Clinical Diagnosis of Neovascular Glaucoma in the Ophthalmology Office
ible NVA on gonioscopy. As the disease progresses, the IOP rises even though the angle may still appear to be open; these eyes are often responsive to medical IOP-lowering therapy since the trabecular meshwork may still be partially functional. As the disease progresses, synechial angle closure develops and the IOP becomes less responsive to medical IOP-lowering therapy; surgical IOP-lowering intervention is often needed at this stage.
3.4 Conjunctiva/Sclera and Cornea Conjunctival hyperemia and ciliary flush may be seen in NVG, especially during acute elevations of IOP. Microcystic corneal edema may also be observed with acute IOP elevations. However, the cornea may be clear despite extremely elevated IOP, typically if the IOP increase has been gradual or chronic, and this may be associated with worse outcomes if it is an indication of long- term IOP elevation that has had a longer amount of time to cause severe glaucomatous optic neuropathy.
3.5 Anterior Chamber Bleeding from NVI can lead to microhyphema or hyphema. Mild anterior chamber inflammation can also be observed. In advanced disease where the angle has become synechially closed, the anterior chamber may appear to be shallow due to the broad PAS.
3.6 Iris Examination of the iris prior to dilation is critical to assess for NVI (rubeosis iridis). Neovascularization is usually first noted at the pupillary border. Whereas normal iris vessels usually lie in the stroma and are radial in orientation, neovessels appear on the iris surface and do not follow an organized growth pattern. Early, subtle neovascularization is best detected using
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the high-magnification setting on the slit lamp. Corectopia and ectropion uveae may be noted in advanced stages due to peripheral anterior synechiae and contraction of the fibrovascular membrane that forms over the iris. This membrane may also give a smooth, glistening appearance to the iris. NVG can also lead to posterior synechiae or an inflammatory membrane at the pupil margin; if present for 360°, posterior synechiae can even lead to pupillary block and iris bombe configuration.
3.7 Gonioscopy Gonioscopy is critical in the assessment of NVG and should be performed prior to dilation. Although NVA usually develops after NVI, in some cases NVA can be seen without any NVI at the pupillary border [15]. In the Central Vein Occlusion Study (CVOS), for example, 10% of eyes with nonischemic CRVO and 6% of eyes with ischemic CRVO developed NVA without apparent NVI [16]. It is therefore critical to perform gonioscopy in patients with NVG or those who are at risk for it due to underlying retinal disease such as PDR and CRVO, even when no NVI is noted. Gonioscopy is crucial even in the absence of elevated IOP, as it may help detect NVA that warrants more aggressive treatment of the underlying retinopathy. In early stages of NVG, neovessels appear over the angle structures but the angle still appears open. As the disease progresses, peripheral anterior synechiae develop and lead to synechial angle closure. Indentation gonioscopy may reveal that an angle that appeared to be completely synechially closed may in fact be open in some areas with indentation, revealing NVA adjacent to areas of PAS.
3.8 Lens Examining the lens status can help with treatment planning. The presence of a visually significant cataract could be a sign that combined cataract and glaucoma surgery would be benefi-
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cial. In eyes with history of intravitreal injection, assessing for inadvertent needle violation of the lens capsule can prevent unanticipated intraoperative events. If the eye is pseudophakic, noting whether the intraocular lens is in the capsular bag, sulcus, or anterior chamber may also assist with surgical planning.
3.9 Dilated Fundus Examination In some cases, vitreous hemorrhage may obscure the view of fundus details, and an ultrasound examination may be helpful to assess for retinal breaks, retinal detachment, or posterior pole masses. If a view is possible, glaucomatous changes of the optic nerve may be noted on dilated fundus examination, including increased cup-to-disc ratio, focal notching, disc hemorrhage, or atrophy of the retinal nerve fiber layer. However, elevated IOP may not have been present with enough severity or duration to cause any signs of glaucomatous structural change. It is critical to examine the optic nerve in both eyes to assess for possible asymmetry. Glaucomatous optic nerve damage in the other eye of a patient with NVG secondary to CRVO in the eye in question may suggest that the CRVO was a result of uncontrolled primary open angle glaucoma. The optic nerve exam may also reveal pallor and fine vessels on the nerve head consistent with neovascularization of the disc. These changes may be driven by the underlying ischemic retinal disease or panretinal photocoagulation that was performed to treat PDR or CRVO. A thorough dilated fundus examination also enables identification of possible underlying etiologies for NVG, including PDR (neovascularization of the disc or neovascularization elsewhere), old CRVO (optociliary shunt vessels, vessel sheathing), or ocular ischemic syndrome (mid-peripheral retinal hemorrhages). Presence of tractional retinal detachment in PDR or other disease that could require silicone oil for repair may impact surgical planning, such as placement
I. F. Aboobakar and M. M. Lin
of an aqueous shunt in an inferior rather than superior quadrant.
4 Ancillary Testing While NVG is primarily a clinical diagnosis, ancillary testing can help assess the degree of glaucoma damage and identify underlying etiologies. Important tests that may be performed in the outpatient clinic setting are highlighted below.
4.1 Anterior Segment Photography Anterior segment photographs prior to dilation may aid in the detection and documentation of NVI and could be particularly helpful in retina clinics where patients may often only be examined by the physician after dilation. Automated gonioscopy has the potential to circumferentially document the angle status, though it is not a perfect substitute for dynamic gonioscopy by a skilled examiner.
4.2 Visual Field Testing Visual field testing using standard automated perimetry is a cornerstone of glaucoma diagnosis, assessment of disease severity, and monitoring for progression [17–19]. However, corneal edema, macular edema, macular ischemia, vitreous hemorrhage, or underlying retinal disease may limit the utility of visual field testing. Modifications such as using size V stimulus may improve the chances that visual field testing will provide useful information. Distinguishing whether field loss is due to glaucoma or other causes can be challenging. Glaucomatous field defects respect the horizontal meridian and classically present as a nasal step, arcuate scotoma, or with generalized depression in advanced disease. It is important to note that visual field loss in NVG patients can also be due to underlying retinal disease or its treatment (e.g., panretinal photocoagulation) [20].
Clinical Diagnosis of Neovascular Glaucoma in the Ophthalmology Office
4.3 Optical Coherence Tomography (OCT) OCT provides high-speed, high-resolution imaging of the retinal nerve fiber layer (RNFL) and ganglion cell layer, which may be damaged before visual field defects are noted in glaucoma [21, 22]. It is critical to obtain a baseline OCT and assess for change over time. Of note, the presence of macular edema or other retinal pathology can affect thickness measurements and must be taken into account when interpreting data [23]. In particular, at initial presentation of NVG, disc edema may cause RNFL measurements to be artificially thickened, and macular edema may make ganglion cell layer segmentation challenging. As the inflammation and edema resolve, repeated OCT scans may indicate RNFL thinning, but this may be from resolution of edema instead of true glaucomatous progression. Optical coherence tomography angiography (OCT-A) has potential to aid in detection of NVI before it is visible clinically [24, 25]. OCT-A relies on detecting changes between rapidly repeated OCT scans of the same area, highlighting vascular areas where moving red blood cells will vary in appearance between images. This noninvasive technology does not require intravascular dyes, but it is not as widely available as standard OCT.
4.4 Fluorescein Angiography Fluorescein angiography (FA) is useful in imaging the retinal and choroidal vasculature and helps in the diagnosis of pathologic processes of the retina. It can be helpful for identifying an underlying etiology for NVG. In patients with PDR, FA leakage may be noted from the disc due to NVD or elsewhere in the retina due to NVE. In CRVO, perivenular hypoautofluorescence is seen due to autofluorescence blockage from hemorrhages and inner retinal edema [26]. Iris angiography is not widely utilized clinically, but it may be helpful
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in the detection of subtle NVI before it becomes evident on slit-lamp biomicroscopy [27].
4.5 B-Scan Ultrasound If no posterior view is possible on exam, a B-scan ultrasound should be performed to evaluate for posterior pathology, including vitreous hemorrhage, mass, or retinal detachment that may require additional treatment by a retina specialist. A suspicious mass may require additional neoplastic workup and would suggest that cyclophotocoagulation would be more appropriate than an aqueous shunt which could risk extraocular tumor spread. Retinal detachment may alter surgical urgency, and it is important to consider whether gas or silicone oil will be used.
4.6 Systemic Workup Laboratory and radiology workup may be needed to identify an underlying systemic etiology for the development of NVG. This may include a blood glucose or hemoglobin A1c to evaluate for diabetes; a hypercoagulable workup in young patients with CRVO and no vascular risk factors; or a carotid doppler ultrasound to evaluate for carotid occlusive disease and ocular ischemic syndrome. This workup may be coordinated with the patient’s primary care provider or performed in the emergency room depending on the clinical urgency.
5 Treatment Once a clinical diagnosis of NVG has been made, prompt treatment is critical. Treatment of NVG will be covered in detail in other chapters, but in brief, the cornerstones of treatment involve controlling IOP with medications and/or surgery, as well as treating the underlying retinal disease, typically with a combination of intravitreal injections and panretinal photocoagulation.
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6 Conclusion Careful history taking, examination, and ancillary testing are critical in the clinical diagnosis of NVG. As many patients with NVG are asymptomatic, especially in the early stages, it is important to have a high suspicion for NVG in patients with predisposing conditions such as PDR and CRVO and to perform appropriate examination including gonioscopy. As the disease progresses, previously asymptomatic patients may develop severe pain and/or decreased vision which may prompt them to seek urgent medical attention in an emergency room setting, which will be discussed in detail in the next chapter.
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Clinical Diagnosis of Neovascular Glaucoma in the Emergency Room Christos N. Theophanous and Katy C. Liu
1 Disease Pathogenesis
2 Clinical Presentation
In patients with neovascular glaucoma (NVG), an acute rise in intraocular pressure (IOP) often prompts a visit to the emergency room because patients experience severe pain and/or decreased vision. Acute IOP elevation in NVG is often due to neovascularization of the angle (NVA) which obstructs aqueous outflow through the trabecular meshwork; as the disease progresses, peripheral anterior synechiae can develop and cause synechial angle closure [1]. Acute IOP elevation in NVG can also occur due to hyphema secondary to neovascularization of the iris (NVI) in the absence of NVA [2]. Patients with NVG may also present to the emergency room with visual symptoms related to underlying retinal neovascularization such as macular edema or vitreous hemorrhage.
The acute onset of symptoms in NVG can be a manifestation of previously undiagnosed disease or varying stages of the disease course. Common presenting symptoms include blurry vision, eye pain, eye redness, tearing, photophobia, or ocular irritation [3]. Ocular symptoms may also be associated with headache, nausea, and vomiting. In some cases, the presenting symptoms at different stages of NVG can be indistinguishable. For instance, a patient presenting with blurry vision may have decreased vision due to microcystic corneal edema in the setting of acute IOP elevation, obscuration from hyphema or vitreous hemorrhage, macular edema secondary to underlying retinal pathology, or acute ischemia from a retinal vessel occlusion. Blurry vision may also be due to glaucomatous optic neuropathy in later stages of NVG. In cases with more indolent and gradual IOP elevation, the patient may not complain of eye redness, pain or photophobia, but rather, presentation to the emergency room may be preceded by slow, painless vision loss.
C. N. Theophanous Department of Ophthalmology and Visual Science, University of Chicago, Chicago, IL, USA K. C. Liu (*) Department of Ophthalmology, Duke University, Durham, NC, USA e-mail: [email protected]
3 Patient History Given the variety of possible presenting symptoms and the spectrum of underlying causes for NVG, it is critical to obtain a detailed history with the following key elements:
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1. Elicit the Nature of Symptoms. A careful history should include characterization of symptom quality, onset, duration, and associated signs or symptoms. Pertinent history-taking can suggest symptom etiology or the extent of disease. For example, eye pain characterized as deep, aching pain with or without headaches, nausea and vomiting, or halos around lights is more likely related to acute IOP elevation, whereas ocular irritation or foreign body sensation is more likely secondary to microcystic corneal edema. If eye pain or redness is present, it is useful to elicit whether the symptoms developed suddenly or gradually, which can suggest rapid versus gradual IOP elevation, respectively. If presenting symptoms are associated with preceding transient visual loss, i.e., amaurosis fugax, the history may indicate ocular ischemic syndrome (OIS) as an underlying etiology [4]. It is also important to ask about symptoms in the fellow eye. Since visual outcomes can be poor in many cases of NVG, identification of early or subtle changes in the fellow eye can facilitate closer monitoring and early intervention. 2. Elicit the Timing of Symptoms. The temporal relationship between symptoms can suggest underlying causes for NVG. For instance, sudden vision loss months before presentation could suggest NVG secondary to a central retinal vein occlusion (CRVO), whereas more recent vision loss weeks prior to presentation could favor NVG due to an underlying central retinal artery occlusion (CRAO) [5]. In patients with proliferative diabetic retinopathy (PDR), the onset of NVG is usually associated with periods of uncontrolled hyperglycemia [3]. 3. Elicit a Thorough Medical History. Vasculopathic or ischemic systemic risk factors should raise concern for NVG. In particular, it is important to inquire about hypertension, hyperlipidemia, coronary artery disease, diabetes mellitus, history of cerebrovascular accident, coagulopathies, autoimmune conditions, vasculitis, and carotid occlusive disease. The degree of control of these medical conditions can correlate with
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onset or worsening of NVG. For instance, poor glycemic control, uncontrolled hypertension, or recent vasculitis flares can lead to retinal ischemia and predispose to new onset or worsening NVG. Oncologic history should also be solicited as the presence of tumors or a history of head and neck radiation are risk factors for NVG. For surgical planning purposes, it is also helpful to inquire about use of aspirin or anticoagulant medications. 4. Elicit a Complete Ocular History. Given the variety of underlying ischemic etiologies that can result in NVG, known history of PDR, CRAO, CRVO, OIS, or other less common ischemic conditions should raise concern for NVG [6]. If the patient cannot recall specific ocular diagnoses, a history of retinal laser or intravitreal injections (i.e., anti-vascular endothelial growth factor (anti-VEGF) injections) may indicate prior treatments for retinal ischemia. A history of vitrectomy surgery should be elicited, as NVG can result from chronic retinal detachment, and eyes with PDR may have previously undergone pars plana vitrectomy. It is also helpful to inquire about a history of glaucoma or the use of IOP-lowering medications.
4 Physical Examination The diagnosis of neovascular glaucoma can usually be confirmed by a careful physical examination. The following clinical signs are useful in the diagnosis of NVG: 1. Vitals and Medical Examination. Patients seen in the emergency room have generally undergone a full medical examination prior to consultation. Vitals should be reviewed with attention to elevated blood pressure indicating underlying hypertension. Laboratory values such as blood glucose and hemoglobin A1c (HbA1c) can be diagnostic for diabetes and the degree of control. A comprehensive physical examination can elicit signs of vasculopathy. For patients with suspected OIS, auscultation for carotid bruits
Clinical Diagnosis of Neovascular Glaucoma in the Emergency Room
should be specifically performed. Notably, the patient’s medical status is important for treatment planning; if the patient is being treated for more emergent or life-threatening conditions (e.g., hypertensive emergency or electrolyte imbalance from missed dialysis), or if the patient’s condition prohibits anesthesia clearance for surgery, the glaucoma management may need to be modified accordingly. 2. Visual Acuity and Pupil Exam. Patients with NVG often present with poor visual acuity. A baseline visual acuity is useful, but there can be limitations to acquiring an accurate visual acuity assessment in the emergency room including lack of access to a Snellen chart, appropriate lighting, spectacles if checking near vision, and limited patient cooperation. Nonetheless, even an estimate of visual acuity can help guide treatment planning. For instance, very poor baseline vision, especially no light perception vision, may push treatment toward less invasive options such as transscleral cyclophotocoagulation over an incisional glaucoma surgery. Next, a careful pupillary exam should be performed prior to dilation to assess for pupillary response. The affected pupil can be poorly reactive in NVG, and it is also important to check for the presence of a relative afferent pupillary defect (RAPD). Notably, a RAPD may indicate a glaucomatous optic neuropathy, but a RAPD can also be present in other conditions such as an ischemic CRVO. In cases where the view to the pupil is obstructed, such as with significant hyphema or microcystic edema, assessment of RAPD can be performed by reverse testing of the unaffected eye. 3. Intraocular Pressure. Measuring IOP in the affected and contralateral eye is critical in the evaluation of NVG in the emergency room. IOP can stratify the acuity of the clinical presentation and the extent of disease. Of note, IOP is not always elevated in the affected eye; higher IOP in the contralateral eye can be suggestive of NVG secondary to OIS. In the emergency room setting, Goldmann
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applanation tonometry may not be available or logistically feasible. Portable handheld tonometers such as a Tono-Pen® (Reichert, Depew, NY) or an iCare (iCare USA, Raleigh, NC) may be practical and are generally sufficient for IOP measurement in the emergency room setting. 4. Confrontational Visual Fields. Assessment of visual fields in the emergency room is important, as the patient may not appreciate monocular field changes in the affected eye. Retinal ischemia or advanced glaucoma can impact the visual field. Field defects can be suggestive of branch or hemiretinal vessel occlusion, and peripheral field loss may indicate advanced glaucoma. Notably, accurate visual field assessment in the acute setting may be limited by a variety of factors such as microcystic edema of the cornea, dense hyphema, or vitreous hemorrhage. In cases with microcystic edema, it is prudent to delay or repeat confrontational visual field evaluation after the IOP has been lowered. 5. Conjunctival Examination. Conjunctival hyperemia and ciliary flush can be observed in NVG patients, especially those with an acute rise in IOP. The conjunctiva should also be examined for evidence of prior glaucoma surgeries (i.e., trabeculectomies, aqueous shunts, or other implants such as XEN® Gel Stents (Allergan, Dublin, Ireland) or Ex- PRESS Shunts (Alcon Laboratories Inc., Fort Worth, TX)) which may inform the patient’s prior ocular history and guide surgical management decisions. 6. Corneal Examination. Corneal changes such as microcystic edema can be an indication of rapid IOP elevation and blur the view for a detailed ocular examination. If microcystic edema is present in the setting of high IOP, initial topical treatment with beta-adrenergic antagonists, carbonic anhydrase inhibitors, and alpha-2 agonists can help to reduce edema and improve the view. Of note, prostaglandin analogs are often avoided to prevent further breakdown of the blood-aqueous barrier and worsening inflammation. Similarly, anticholinergics are proinflamma-
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tory which can worsen peripheral anterior synechiae formation and are generally contraindicated [7]. If microcystic edema limits the initial exam, an updated examination after resolution of the edema can reveal subtle and previously concealed anterior and posterior segment exam findings. 7. Anterior Chamber Examination. A hyphema or microhyphema may suggest the presence of anterior segment neovascularization. Suspicion for underlying NVI and NVA should be particularly high in cases of seemingly spontaneous hyphema in the absence of trauma or other predisposing factors such as uveitis-glaucoma-hyphema syndrome in a pseudophakic eye. Mild anterior chamber reaction may be present in some cases. 8. Iris Examination. Neovascularization of the iris, or rubeosis, is a hallmark feature of NVG, though it is possible to have NVA and elevated IOP without NVI. Fine blood vessels can be seen on the surface of the iris and typically grow in a meandering pattern, extending from the pupillary margin. In some cases of acutely high IOP, NVI may appear less visible until the IOP is lowered and there is less resistance to vessel filling. In chronic NVG, ectropion uveae can be present due to contraction of the fibrovascular membrane. In cases of chronic, mature NVI, iris vessels may persist even after treatment for neovascularization, but typically appear less engorged than before. Regressed NVI can appear as either an absence of previously noted vessels, white empty-appearing ghost vessels on the iris surface, or an avascular fibrous membrane. Importantly, the fellow eye should be carefully examined for active or regressed NVI. 9. Gonioscopy and Iridocorneal Angle Examination. Assessment of the angle by gonioscopy should ideally be performed prior to dilation. Gonioscopic findings in NVG include neovascularization of the angle (NVA), peripheral anterior synechiae, and/or small-layered hyphema in the inferior angle
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that may not be large enough to observe on slit-lamp examination without the gonioprism. Usually, NVA develops later than NVI, although NVA can be present when NVI is not seen. Notably, if the patient is receiving anti-VEGF injections, active neovascularization may not be present. It is also critical to evaluate angle structures to determine the extent of angle closure. NVA can progress to peripheral anterior synechiae formation which, in later stages of the disease, can lead to synechial angle closure. It is critical to perform compression gonioscopy in suspected NVG; in angles that initially appear closed without visible NVA, indentation can reveal NVA in the deepened angle, confirming the diagnosis of NVG. The absence of angle structures that does not deepen with significant compression indicate a synechially closed angle. The ability to perform gonioscopy may be limited in the emergency room setting due to a lack of available equipment or a poor view to the angle. Examination of the fellow eye is important to assess for asymmetric findings. If microcytic edema impairs the view to perform gonioscopy, a repeat exam following IOP reduction is recommended. Hypertonic saline drops may also provide enough temporary improvement in corneal edema to allow for a sufficient gonioscopic exam. 1 0. Funduscopic Examination. A careful funduscopic exam can reveal signs of the underlying etiology for the NVG. Pertinent exam findings include retinal hemorrhages, neovascularization of the disc or elsewhere, cystoid macular edema, vessel abnormalities (e.g., attenuation, tortuosity, dilation), emboli, cotton wool spots, or vitreous hemorrhage. Examination of the optic nerve may show glaucomatous cupping depending on the duration and degree of IOP elevation. Evaluation of the degree of optic nerve head cupping may be confounded by a variety of factors in NVG patients. In the acute setting, disc edema may mask the degree of cupping.
Clinical Diagnosis of Neovascular Glaucoma in the Emergency Room
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The neuroretinal rim may be difficult to iden- 6 Treatment and Follow-Up tify with disc neovascularization that can obscure its contours, or by the presence of After the initial diagnostic workup for NVG is optic nerve pallor from an ischemic- complete, a treatment and follow-up plan should underlying etiology. Visualization of the be formulated. Immediate interventions to be nerve may also be obscured during the initial performed in the emergency department depend examination by microcystic edema, on a variety of factors including specialist availhyphema, or vitreous hemorrhage. Dilated ability, severity of the patient’s glaucoma, institufunduscopic examination of both eyes should tional practice patterns, and the patient’s medical be performed, as comparing the two eyes can comorbidities, among others. Broadly, however, aid in diagnosis of NVG in the affected eye attempts should be made to lower IOP before the as well as prognosis for developing NVG in patient is discharged from the emergency departthe fellow eye. Importantly, patients may ment. Immediate IOP lowering generally consists have NVG bilaterally but only complain of of repeated rounds of topical IOP-lowering medisymptoms in the worse-seeing eye. In those cations and oral or intravenous agents such as cases, close monitoring and/or early treat- acetazolamide or mannitol. In refractory cases, ment of the better-seeing eye will be critical anterior chamber paracentesis could be considin terms of the patient’s long-term visual ered while weighing the risk of causing or worsfunction. ening a hyphema. If possible, anti-VEGF intravitreal injections can be administered in the emergency department, although this capability 5 Additional Testing will depend on the hospital level of care, availability of retina service coverage, and other facFurther testing may be helpful if findings remain tors. Patient factors such as medication adherence, inconclusive, ophthalmic examination is limited, lack of transportation, and other barriers to folor suspected etiologies warrant additional low-up, and insurance status should also be taken workup. If there is limited view of the fundus, into consideration in the treatment plan. For B-scan ultrasonography should be used to evalu- instance, performing surgical intervention, intraate for vitreoretinal abnormalities such as vitre- vitreal injections, or panretinal photocoagulation ous hemorrhage or retinal detachments. If a treatment during the emergency department visit computed tomography (CT) scan was ordered as might be warranted for patients with barriers to diagnostic workup for a coexisting complaint timely outpatient follow-up. Once the patient is (e.g., headache), neuroimaging may show vitre- stabilized, close outpatient follow-up should be ous opacities or gross retinal pathology. The made with the appropriate glaucoma and retina resources of the emergency department may be specialists for further workup and management. particularly beneficial when workup or testing The specific outpatient treatment options are discan be performed more quickly than in an outpa- cussed more thoroughly in a different chapter. tient setting. For instance, doppler ultrasound should be ordered if findings suggest OIS and underlying carotid occlusive disease. Laboratory 7 Conclusions tests can also be performed more easily in the emergency department. Depending on the clini- NVG patients often present to the emergency cal context, pertinent diagnostic laboratory tests room with significant symptoms and visual can include blood glucose, HbA1c, complete changes. Careful history taking, review of mediblood count (CBC), erythrocyte sedimentation cal records, and examination of both the affected rate (ESR), C-reactive protein (CRP), coagula- and fellow eyes are critical to diagnosis of NVG tion factors, or autoimmune markers. and its underlying condition as well as determi-
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nation of a suitable treatment plan. Both resource limitations in the emergency room and the potential presence of other active health issues may make evaluation more challenging than in the outpatient setting. Strategies should be employed to acquire the best assessment of the affected and fellow eyes as possible. Emergency room treatment should seek to quickly reduce the IOP, provide initial treatment for the underlying disease process, as reasonable, and a follow-up plan should be developed with attention to patient factors and circumstances.
References 1. Yang H, Yu X, Sun X. Neovascular glaucoma: handling in the future. Taiwan J Ophthalmol. 2018;8(2):60–6. 2. Hayreh SS. Neovascular glaucoma. Prog Retin Eye Res. 2007;26(5):470–85.
C. N. Theophanous and K. C. Liu 3. Rodrigues GB, Abe RY, Zangalli C, Sodre SL, Donini FA, Costa DC, Leite A, Felix JP, Torigoe M, Diniz- Filho A, de Almeida HG. Neovascular glaucoma: a review. Int J Retina Vitreous. 2016;14(2):26. 4. Mizener JB, Podhajsky P, Hayreh SS. Ocular ischemic syndrome. Ophthalmology. 1997;104(5):859–64. 5. Duker JS, Sivalingam A, Brown GC, Reber R. A prospective study of acute central retinal artery obstruction. The incidence of secondary ocular neovascularization. Arch Ophthalmol. 1991;109(3):339–42. 6. Shazly TA, Latina MA. Neovascular glaucoma: etiology, diagnosis and prognosis. Semin Ophthalmol. 2009;24(2):113–21. 7. Havens SJ, Gulati V. Neovascular glaucoma. Dev Ophthalmol. 2016;55:196–204.
Neovascular Glaucoma in Proliferative Diabetic Retinopathy Jing Shan, Chu Jian Ma, and Catherine Q. Sun
1 Introduction
2 Epidemiology
Neovascular glaucoma (NVG) most commonly occurs in the setting of retinal ischemia after development of proliferative diabetic retinopathy (PDR) [1]. Management of elevated intraocular pressure (IOP) secondary to NVG usually requires IOP-lowering medications and often also requires IOP-lowering surgery. Management of the underlying PDR usually requires a combination of antivascular endothelial growth factor (VEGF) injections and panretinal photocoagulation (PRP). Despite a multifaceted therapeutic approach that includes temporizing and permanent measures, the prognosis is often poor [2]. The advancements in diabetes and retinal treatment in the last few decades have increased therapeutic options for patients at risk of PDR and subsequent NVG. However, the detection and management of NVG still have substantial room for improvement.
2.1 Neovascular Glaucoma
J. Shan · C. J. Ma Department of Ophthalmology, University of California, San Francisco, CA, USA C. Q. Sun (*) Department of Ophthalmology, University of California, San Francisco, CA, USA Frances I. Proctor Foundation, University of California, San Francisco, CA, USA e-mail: [email protected]
NVG occurs in a small percentage of patients with diabetic retinopathy. In the 2016 Intelligent Research in Sight (IRIS®) Registry, the prevalence of NVG in the dataset was 0.23 per 100 patients, which is estimated to be 3% of all glaucoma patients in the dataset (excluding glaucoma suspects) [3]. Studies have found that among PDR patients, those with NVG tend to be younger (50.8 years vs. 56.1 years), have shorter duration of diabetes (9.2 years vs. 13.7 years) and higher hemoglobin A1c (HbA1c) (8.3% vs. 7.5%) than PDR patients without NVG [4]. Few studies have focused on the epidemiology of NVG, but there is more robust literature on the epidemiology and risk factors of diabetic retinopathy.
2.2 Proliferative Diabetic Retinopathy In the United States (US) and globally, diabetes is a growing concern, affecting about 10% of Americans and 4% of the world’s population [5]. The prevalence of diabetes mellitus (DM) in the US is expected to increase by 54% to more than 55 million Americans from 2015 to 2030, and globally from 463 million adults in 2019 to 578 million adults in 2030, which will have an enor-
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mous health and socioeconomic impact worldwide [6, 7]. PDR occurs in 7% of patients with DM globally [5]. In the US, the number of patients with vision threatening diabetic retinopathy, which includes PDR and diabetic macular edema, are expected to increase from 1.2 million in 2005 to 3.4 million in 2050 [8]. The prevalence of PDR is higher in those with type 1 DM (32%), compared to those with type 2 DM (3%) [9]. Other notable differences include a younger age of PDR onset for type 1 DM patients; studies have reported the mean age of onset of PDR to be between 34.9 and 38.0 years for type 1 DM patients and between
56.8 and 65.3 years for type 2 DM patients [10– 14]. The difference in age of onset of PDR is likely related to the duration of the underlying diabetes, which is a major risk factor for development of diabetic retinopathy. The Los Angeles Latino Eye Study found that 18% of participants with type 1 or 2 DM for more than 15 years had PDR [15]. Similarly, the Wisconsin Epidemiologic Study of Diabetic Retinopathy found that PDR develops in 2% of type 2 DM patients with diabetes duration of less than 5 years and in 25% of type 2 DM patients with diabetes duration of 25 years or more [16]. Table 1 summarizes the pivotal studies relevant to diabetic retinopathy.
Table 1 Pivotal diabetic retinopathy studies Study name Interval Study design Systemic diabetes mellitus studies United Kingdom 1977– RCT Prospective 1991 Diabetes Study (UKPDS) [77, 78]
Wisconsin Epidemiologic Study of Diabetic Retinopathy [16, 79, 80]
1980– 2007
Population- based cohort study
Patient population
Intervention
Newly diagnosed type 2 DM N = 5102 patients enrolled
Intensive (medication) vs. conventional (diet) glycemic control
Diabetic patients in southern Wisconsin N = 2990 patients sampled at baseline
Observation
Study conclusions (relevant to PDR) • Intensive therapy arm had mean HbA1c of 7.0% (compared to 7.9% in conventional) and reduction in microvascular complications (DR and nephropathy) but not macrovascular disease • Intensive therapy arm had 25% reduction in need for PRP Incidence and progression of DR, and progression to PDR were highest in the group diagnosed before age 30. • DR occurred in type 1 DM patients 3–5 years after diagnosis and almost all patients were affected by 25 years (97%) • 25-year cumulative rate of progression to PDR was 42% in type 1 DM • Strongest relationship to DR progression was worse glycemic control
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Neovascular Glaucoma in Proliferative Diabetic Retinopathy Table 1 (continued) Patient population Type 1 DM N = 1441 patients enrolled
Study name Diabetes Control and Complications Trial (DCCT) [81–83]
Interval Study design 1984– RCT 1993
Intervention Intensive vs. conventional glycemic control
Epidemiology of Diabetes Interventions and Complications Trial (EDIC) [84, 85]
1994– 2013
Prospective cohort study
All participants of DCCT N = 1375 patients participated
All initiated intensive glycemic control
Los Angeles Latino Eye Study [86, 87]
2000– 2008
Population- based cohort study
Adult Latinos (≥40 years) in Los Angeles County N = 6357 patients participated at baseline
Observation
Action to Control Cardiovascular Risk in Diabetes (ACCORD) [88, 89]
2001– 2009
RCT
Type 2 DM and high risk of cardiovascular disease N = 10,251 patients enrolled
Intensive (goal HbA1c